The cytokine TRAIL is capable of specifically inducing apoptosis in tumor cells without affecting non-transformed cells and, thus is considered as a valuable effector molecule for therapy of cancer and other diseases. Unlike other members of the tumor necrosis factor (TNF) superfamily, e.g. TNF or CD95L, TRAIL is well tolerated upon systemic application, which facilitates the development of TRAIL-based biopharmaceuticals. TRAIL activates the extrinsic apoptotic pathway via binding to death receptors (DR) 4 and 5 which leads to cell death of tumor cells. Nevertheless, effective tumor eradication upon triggering of death receptors is hampered by intracellular resistance mechanisms and low bioactivity of conventional TRAIL biopharmaceuticals. Different therapeutic strategies dealing with DR activation have been developed. Agonistic monoclonal antibodies directed against either DR4, such as Mapatumumab or DR5, e.g. Conatumumab and Lexatumumab have been tested in phase I or phase II clinical studies with ambiguous results (for review see Holland et al. 2014; Micheau et al., 2013). Furthermore, soluble forms of TRAIL such as dulanermin (Herbst et al., 2010 a, b) and a circularly permuted TRAIL (CPT, Chen et al., 2012a) have been studied in several clinical trials. Although the combination of recombinant TRAIL with chemotherapeutics, e.g. thalidomide (Chen et al., 2012b) has led to more promising results than the monotherapy with the recombinant product, current forms of TRAIL are still associated with disadvantages, particularly a short half-life in the blood circulation, which does not exceed one hour. Thus, as a first step to overcome TRAIL-associated limitations, a single-chain format featuring three TRAIL modules (amino acid residues 95-281) connected by Gly/Ser peptides of 16, respectively 8 residues was developed, which has been shown to be more stable compared with soluble TRAIL (unpublished data; Schneider et al., 2010; Siegemund et al., 2012). Moreover, single-chain TRAIL can also be used for generation of antibody TRAIL fusion proteins. The homotrimeric TRAIL is naturally expressed as a membrane protein, which can also be present in a proteolytically cleaved, soluble form. This soluble form can induce apoptosis in tumor cells mainly via triggering the death receptor 4 (DR4) mediated extrinsic pathway, while a full activation of the apoptosis machinery involving an activation of death receptor 5 (DR5) still demands an oligomeric presence or localization of TRAIL at the plasma membrane. Since a therapeutic application of TRAIL should be based on a soluble protein, additional strategies are needed to mimic the bioactivity of membrane-localized TRAIL. The fusion of TRAIL or single-chain TRAIL to recombinant antibody formats, e.g. scFvs or diabodies, is an appropriate way to achieve a cell surface targeting, taking tumor specific markers into account (for review see de Bruyn et al., 2013)). Such TRAIL fusion proteins have been shown to express higher tumor specificity and an increased serum half-life compared with soluble TRAIL (Schneider et al., 2010). However, even the single-chain variants of TRAIL described so far exhibit a rather low thermal stability, with melting points of approximately 46-47° C. as determined by dynamic light scattering, which can affect therapeutic activity and stability during production and storage. In particular, evidence has been found that higher protein thermostability can directly correlate with an increased serum half-life time, actually representing one of the most requested properties in view of therapeutic applications for recombinant proteins (Gao et al., 2009). Therefore, the development of derivatives of single-chain THDs (scTHDs), in particular single chain TRAILs (scTRAILs) with improved thermal stability and solubility is currently challenging. It has surprisingly been shown by the present inventors that the use of THDs with additional N- and/or C-terminal deletions and distinct mutations at the N- and C-terminus of the THD, in particular TRAIL provides several advantages including inter alia increased solubility of the proteins, increased thermal stability, higher recombinant production rate and higher molecular integrity, e.g. less degradation/chain termination. The use of these improved scTHDs in the diabody-scTHD format, in particular diabody-scTRAIL format provides further benefits for the therapeutic suitability of this format. This format has been further enhanced by including redesigned connecting peptides between VH and VL of the diabody as well as improving the connecting peptides between the diabody and the improved scTHD variants, in particular scTRAIL variants.